tbuckley/cabot-search huggingface dataset:
Abstract 1602: Lineage plasticity enables low ER luminal tumors to evolve and gain basal-like traits
Authors: Gadisti Aisha Nurulhijjah Binti Mohamed, Nevena B. Ognjenovic, Sundis Mahmood, Sarah Min Kyung Lee, Brock C. Christensen, Kristen E. Muller, Diwakar R. Pattabiraman
Journal: Cancer Research (2022)

Abstract Stratifying breast cancer into specific molecular or histological subtypes aids in therapeutic decision-making and predicting outcomes, however, these subtypes may not be as distinct as previously thought. Patients with luminal-like, Estrogen Receptor (ER)-expressing tumors have better prognosis than patients with more aggressive, triple-negative or basal-like tumors. There is, however, a subset of luminal-like tumors that express lower levels of ER, which exhibit more basal-like features. Previous studies have suggested that triple negative, basal-like tumors may arise from a luminal cell-of-origin, but there are no definitive studies that identify the cell-of-origin of these low ER tumors. Analysis of 2208 invasive breast carcinomas from 2012-2020 revealed that 2% of tumors have low ER expression (less than 10% ER positive cells), which are mostly high-grade carcinomas and exhibit basal-like features. TCGA analysis revealed that tumors with lower ER expression (lowest quartile of ER expression) expressed higher basal signature genes as compared to tumors with higher levels of ER expression. This variation within the ER+ subtype and the emergence of basal-like characteristics within low ER tumors suggest that some luminal tumors may evolve into a more basal-like or triple-negative subtype. The luminal mouse mammary tumor, MMTV-PyMT, was used to model low ER human tumors and, similar to the patient tumor samples, basal-like tumor cells were also found within these tumors. Lineage tracing using tissue-specific and inducible Cre recombinase-based labelling was performed to elucidate the lineage-of-origin of these basal-like cells, revealing that these basal-like cells were derived from normal luminal epithelial cells, not basal cells. Our study uncovers the existence of luminal-basal plasticity within tumors of a low ER subtype that enables these cells to transition into a more basal-like state. Understanding the factors that enable this plasticity to occur may reveal opportunities to curb the evolution of more aggressive traits, potentially improving the way breast cancer is currently managed and treated. Citation Format: Gadisti Aisha Nurulhijjah Binti Mohamed, Nevena B. Ognjenovic, Sundis Mahmood, Sarah Min Kyung Lee, Brock C. Christensen, Kristen E. Muller, Diwakar R. Pattabiraman. Lineage plasticity enables low ER luminal tumors to evolve and gain basal-like traits [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1602.
Phase II Study of Venetoclax Added to Cladribine Plus Low-Dose Cytarabine Alternating With 5-Azacitidine in Older Patients With Newly Diagnosed Acute Myeloid Leukemia
Authors: Tapan M. Kadia, Patrick K. Reville, Xuemei Wang, Caitlin R. Rausch, Gautam Borthakur, Naveen Pemmaraju, Naval G. Daver, Courtney D. DiNardo, Koji Sasaki, Ghayas C. Issa, Maro Ohanian, Guillermo Montalban-Bravo, Nicholas J. Short, Nitin Jain, Alessandra Ferrajoli, Kapil N. Bhalla, Elias Jabbour, Koichi Takahashi, Rashmi Malla, Kelly Quagliato, Rashmi Kanagal-Shamanna, Uday R. Popat, Michael Andreeff, Guillermo Garcia-Manero, Marina Y. Konopleva, Farhad Ravandi, Hagop M. Kantarjian
Journal: Journal of Clinical Oncology (2022)

The combination of venetoclax and 5-azacitidine (5-AZA) for older or unfit patients with acute myeloid leukemia (AML) improves remission rates and survival compared with 5-AZA alone. We hypothesized that the addition of venetoclax to cladribine (CLAD)/low-dose araC (low-dose cytarabine [LDAC]) alternating with 5-AZA backbone may further improve outcomes for older patients with newly diagnosed AML.This is a phase II study investigating the combination of venetoclax and CLAD/LDAC alternating with venetoclax and 5-AZA in older (≥ 60 years) or unfit patients with newly diagnosed AML. The primary objective was composite complete response (CR) rate (CR plus CR with incomplete blood count recovery); secondary end points were overall survival, disease-free survival (DFS), overall response rate, and toxicity.A total of 60 patients were treated; median age was 68 years (range, 57-84 years). By European LeukemiaNet, 23%, 33%, and 43% were favorable, intermediate, and adverse risk, respectively. Fifty-six of 60 evaluable patients responded (composite CR: 93%) and 84% were negative for measurable residual disease. There was one death (2%) within 4 weeks. With a median follow-up of 22.1 months, the median overall survival and DFS have not yet been reached. The most frequent grade 3/4 nonhematologic adverse events were febrile neutropenia (n = 33) and pneumonia (n = 14). One patient developed grade 4 tumor lysis syndrome.Venetoclax and CLAD/LDAC alternating with venetoclax and 5-AZA is an effective regimen among older or unfit patients with newly diagnosed AML. The rates of overall survival and DFS are encouraging. Further study of this non-anthracycline-containing backbone in younger patients, unfit for intensive chemotherapy, as well as comparisons to standard frontline therapies is warranted.
Abstract 2501: Identification and characterization of key players in the Ewing Sarcoma metastatic process
Authors: Sara Sanchez Serra, Mariona Chicon Bosch, Judith Besalú Velazquez, Susana Maqueda Marcos, Paola Monaco, Laura Santana Viera, Roser Lopez Alemany, Oscar M. Tirado
Journal: Cancer Research (2022)

Abstract Metastasis at diagnosis is the most adverse prognostic factor in Ewing Sarcoma (ES), drastically decreasing patients’ overall survival down to &amp;lt;30%1. However, mechanisms leading to metastasis in this disease remain poorly understood. To deepen our knowledge on the main players in ES metastasis, Microarray (Clariom™ D Array, Affymetrix) and phosphoarray (Phospho Explorer Antibody Arrays, Full Moon Biosystems) analyses were performed on primary tumours (n=5) and metastases (n=12) samples from an spontaneous metastatic ES mouse model2. After normalisation and bioinformatics analysis, a list of differentially expressed genes/proteins between the 2 sample groups was obtained. Candidates were validated by qPCR (TaqMan™ probes) and Western Blot, and further characterised in vitro through loss-of-function phenotypic assays (proliferation, clonogenic and migration) using siRNAs and/or inhibitors. Several genes and proteins of interest, including LOXHD1, confirmed to be overexpressed in metastases samples compared to primary tumours as identified by microarray/phosphoarray analyses and qPCR/Western Blot validation. Also, candidates subjected to transient loss-of-function phenotypic assays significantly decreased in all cases tumorigenic and/or metastatic capabilities of ES cells when suppressed. Additionally, LOXHD1 showed upregulation in sphere-growing ES cells, validating its role in ES hypoxia and metastasis as demonstrated previously3. Using stable knock-out models of the genes of interest, the exact mechanism and pathways in which these candidates play a role in ES metastasis will be further studied in vitro and in vivo. Also, their clinical relevance will be explored in several cohorts of patients by immunohistochemistry on Tissue Microarrays. [1] Grünewald, TGP et al. 2018, Nat Rev Dis Prim, 4(1), pp.1-22. [2] Lagares-Tena, L et al. 2016, Oncotarget, 7(35), pp.56889-903. [3] Deng, Q et al. 2021, bioRxiv 2021.02.22.432287. Citation Format: Sara Sanchez Serra, Mariona Chicon Bosch, Judith Besalú Velazquez, Susana Maqueda Marcos, Paola Monaco, Laura Santana Viera, Roser Lopez Alemany, Oscar M. Tirado. Identification and characterization of key players in the Ewing Sarcoma metastatic process [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2501.
Abstract 1300: Targeted therapies prime lung cancer cells for macrophage-mediated destruction
Authors: Kyle Vacarro, Juliet Allen, Asaf Maoz, Sarah Reeves, Aaron Hata, Kipp Weiskopf
Journal: Cancer Research (2022)

Abstract The CD47/SIRPa axis is an immune checkpoint that regulates macrophage anti-tumor function. Therapies that block CD47 on cancer cells show promise in clinical trials for solid and hematologic malignancies, particularly when combined with other anticancer agents. However, the best combination strategies for using CD47-blocking therapies remain unknown. In this study, we developed a novel in vitro screening platform to identify drugs that render cancer cells more vulnerable to macrophage attack. We performed an unbiased screen of 800 FDA-approved drugs using primary human macrophages and PC9 cells, a human EGFR mutant lung cancer cell line. We identified EGFR tyrosine kinase inhibitors (TKIs) as drugs that act on the cancer cells and specifically enhance macrophage-mediated cytotoxicity (&amp;gt;4-fold enhancement, p&amp;lt;0.01). In contrast, conventional chemotherapy drugs either showed no significant enhancement or abrogated macrophage activation. The combination of EGFR TKIs with anti-CD47 antibodies elicited maximal phagocytosis across a range of cell lines and conditions. In long-term co-culture assays with macrophages, the combination of EGFR TKIs and anti-CD47 antibodies eliminated persister cells to prevent TKI resistance. Importantly, these findings extended to lung cancers with other RTK-MAPK pathway mutations, such as ALK-rearranged cancers (treated with lorlatinib, alectinib, or crizotinib) or KRAS G12C mutant cancers (treated with sotorasib or adagrasib). In xenograft and syngeneic mouse models, the combination of targeted therapies with CD47 ablation was able to dramatically reduce tumor burden. To understand the mechanism of synergy, we generated 8 different lung cancer cell lines resistant to EGFR, ALK, or KRAS inhibitors. The resistant lines significantly upregulated CD47 and concomitantly became more sensitive to macrophage attack in vitro and in vivo. By RNA sequencing, we identified multiple mechanisms contributing to vulnerability, including secretion of the cytokine MIP-3 by the cancer cells and alteration of other immunoregulatory molecules. Overall, we have identified a novel therapeutic strategy to enhance the efficacy of RTK-MAPK pathway inhibitors by combining them with anti-CD47 therapies. Our findings suggest cross-sensitivity occurs such that lung cancer cells that become resistant to targeted therapies also become more sensitive to macrophage attack. Our findings provide rationale for testing this combination approach in patients with lung cancers bearing driver mutations. Citation Format: Kyle Vacarro, Juliet Allen, Asaf Maoz, Sarah Reeves, Aaron Hata, Kipp Weiskopf. Targeted therapies prime lung cancer cells for macrophage-mediated destruction [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1300.
A mechanosensitive lipolytic factor in the bone marrow promotes osteogenesis and lymphopoiesis
Authors: Hui Peng, Biao Hu, Ling-Qi Xie, Tian Su, Chang-Jun Li, Ya Liu, Mi Yang, Ye Xiao, Xu Feng, Rui Zhou, Qi Guo, Hai-Yan Zhou, Yan Huang, Tie-Jian Jiang, Xiang-Hang Luo
Journal: Cell Metabolism (2022)
Novel Subgroups of Type 2 Diabetes Display Different Epigenetic Patterns That Associate With Future Diabetic Complications
Authors: Silja Schrader, Alexander Perfilyev, Emma Ahlqvist, Leif Groop, Allan Vaag, Mats Martinell, Sonia García-Calzón, Charlotte Ling
Journal: Diabetes Care (2022)

OBJECTIVE Type 2 diabetes (T2D) was recently reclassified into severe insulin-deficient diabetes (SIDD), severe insulin-resistant diabetes (SIRD), mild obesity-related diabetes (MOD), and mild age-related diabetes (MARD), which have different risk of complications. We explored whether DNA methylation differs between these subgroups and whether subgroup-unique methylation risk scores (MRSs) predict diabetic complications. RESEARCH DESIGN AND METHODS Genome-wide DNA methylation was analyzed in blood from subjects with newly diagnosed T2D in discovery and replication cohorts. Subgroup-unique MRSs were built, including top subgroup-unique DNA methylation sites. Regression models examined whether MRSs associated with subgroups and future complications. RESULTS We found epigenetic differences between the T2D subgroups. Subgroup-unique MRSs were significantly different in those patients allocated to each respective subgroup compared with the combined group of all other subgroups. These associations were validated in an independent replication cohort, showing that subgroup-unique MRSs associate with individual subgroups (odds ratios 1.6–6.1 per 1-SD increase, P &amp;lt; 0.01). Subgroup-unique MRSs were also associated with future complications. Higher MOD-MRS was associated with lower risk of cardiovascular (hazard ratio [HR] 0.65, P = 0.001) and renal (HR 0.50, P &amp;lt; 0.001) disease, whereas higher SIRD-MRS and MARD-MRS were associated with an increased risk of these complications (HR 1.4–1.9 per 1-SD increase, P &amp;lt; 0.01). Of 95 methylation sites included in subgroup-unique MRSs, 39 were annotated to genes previously linked to diabetes-related traits, including TXNIP and ELOVL2. Methylation in the blood of 18 subgroup-unique sites mirrors epigenetic patterns in tissues relevant for T2D, muscle and adipose tissue. CONCLUSIONS We identified differential epigenetic patterns between T2D subgroups that associated with future diabetic complications. These data support a reclassification of diabetes and the need for precision medicine in T2D subgroups.
Abstract 6370: Assessing the effect of blocking CCL2-CCR2 axis on breast cancer brain metastasis
Authors: Yimin Duan, Yutao Qi, Lin Zhang, Xiangliang Yuan, Dihua Yu
Journal: Cancer Research (2022)

Abstract Among the 300,000 newly diagnosed breast cancer patients every year, 5~20% of them will develop symptomatic brain metastasis, whose 1-year survival rate is lower than 20%. Our group previously reported that brain tumor microenvironment (TME)-mediated PTEN downregulation in brain metastatic tumor cells increases the secretion of the chemokine CCL2, which enhances the infiltration of CCR2+ bone marrow derived myeloid cells, eventually promoting brain metastasis outgrowth. However, the mechanism of CCL2-CCR2 axis promoting brain metastasis is not clear, and the efficacy of targeting either CCR2 or CCL2 remained to be assessed. Here we show that Ccr2 antagonism significantly blocked Ccr2high myeloid cells trafficking in the blood and infiltration into the brain TME. However, Ccr2 antagonism did not sufficiently impede breast cancer brain metastasis in multiple preclinical models. Nevertheless, knocking down CCL2 or targeting CCL2 exhibited significant inhibition of brain metastasis growth. Subsequent analysis of the brain TME through mass cytometry demonstrated dramatically decreased infiltration of both Ccr2high and Ccr2low myeloid cell populations in the CCL2 targeted group, implying that the Ccr2low myeloid cells are also involved in promoting brain metastasis growth. Our data highlights the differential responses between targeting CCR2 or CCL2 in multiple preclinical brain metastasis models, which direct us to explore the function of Ccr2low myeloid cells in regulating brain metastasis progression. Our findings also suggest that carefully choosing between CCR2 or CCL2 as a target to control brain metastasis is important in clinical practice. Citation Format: Yimin Duan, Yutao Qi, Lin Zhang, Xiangliang Yuan, Dihua Yu. Assessing the effect of blocking CCL2-CCR2 axis on breast cancer brain metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6370.
Abstract 5822: Leptin modulated microRNA-628-5p targets Jagged1 and inhibits prostate cancer hallmarks
Authors: Leslimar Rios Colon, Juliet Chijioke, Suryakant Niture, Zainab Afzal, Qi Qi, Anvesha Srivastava, Malathi Ramalinga, Habib Kedir, Patrice Cagle, Elena Arthur, Gagan Deep, Simeng Suy, Sean Collins, Deepak Kumar
Journal: Cancer Research (2022)

Abstract Prostate cancer (PCa) is the most commonly diagnosed non-cutaneous cancer and the second leading cause of cancer deaths in men. Obesity is a major risk factor for prostate cancer. Leptin is an obesity hormone that controls body weight by regulating energy intake and expenditure, and clinical studies have demonstrated a correlation between blood leptin levels and PCa development. MicroRNAs (miRs) are master regulators of cancer cell signaling, including in advanced PCa. We previously identified miR-628-5p as a potential biomarker in PCa patients that was downregulated in serum samples of men with PCa (Tumor Biol., 2014, 35: 4867). In this study, we investigated the link between the obesity hormone leptin and the functional role of miR-628-5p in PCa cell lines. We demonstrate that leptin downregulates the expression of miR-628-5p and increases cell proliferation and migration in PCa cells. Enforced expression of miR-628-5p inhibited cell proliferation in PCa cells. Further, miR-628-5p reduced PCa cell survival/migration/invasion/spheroids formation and cell stemness. Mechanistically, miR-628-5p binds with JAG1-3’UTR and inhibits the expression of Jagged-1 (JAG1). JAG1 inhibition by miR-628-5p also downregulated Notch signaling, decreased the expression of snail/slug, and modulated epithelial-mesenchymal transition and invasiveness in PC3 cells. Furthermore, miR-628-5p increased sensitivity towards enzalutamide and docetaxel by inducing cell apoptosis. Collectively our data suggested that miR-628-5p is a key regulator of PCa carcinogenesis modulated by adipokine leptin and offers a novel therapeutic opportunity to inhibit the growth of advanced PCa. Citation Format: Leslimar Rios Colon, Juliet Chijioke, Suryakant Niture, Zainab Afzal, Qi Qi, Anvesha Srivastava, Malathi Ramalinga, Habib Kedir, Patrice Cagle, Elena Arthur, Gagan Deep, Simeng Suy, Sean Collins, Deepak Kumar. Leptin modulated microRNA-628-5p targets Jagged1 and inhibits prostate cancer hallmarks [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5822.
Combination Antidepressant Therapy vs Monotherapy—Further Considerations—Reply
Authors: Jonathan Henssler, Tom Bschor, Christopher Baethge
Journal: JAMA Psychiatry (2022)

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Abstract 6314: TME subtype impacts response to combined thermal ablation and immunotherapy
Authors: James Wang, Brett Z. Fite, Aris Kare, Bo Wu, Marina N. Raie, Spencer Tumbale, Ryan R. Davis, Clifford G. Tepper, Katherine Ferrara
Journal: Cancer Research (2022)

Abstract The tumor microenvironment (TME) subtype is a critical factor when combining immunotherapy with tumor debulking strategies such as ultrasound ablation. To understand the effects of the TME subtype, we studied two multi-site murine cancer models, an immune-suppressed KPC (Kras+/LSL-G12D; Trp53+/LSL-R172H; Pdx1-Cre) pancreatic adenocarcinoma (MT4) model and a neu deletion HER2+ (NDL) mammary adenocarcinoma model with a larger naïve lymphocyte population. After profiling the two models with histology and single-cell sequencing, we designed immunotherapy combinations with Magnetic Resonance-guided Focused Ultrasound (MRgFUS) thermal ablation that were specific to each TME subtype. To understand the impact of the molecular and cellular differences upon each model, we characterized the treatment effect with transcriptomic analysis and digital cytometry. We found that combining MRgFUS ablation with immunotherapy reduced tumor growth and extended survival by at least 2-fold in the MT4 pancreatic cancer model. Gene set enrichment analysis (GSEA) of bulk RNA sequencing data indicated that the combination of ablation with immunotherapy preferentially enriched functional annotations for leukocyte migration in the MT4 model and wound healing and inflammatory cytokines in the NDL model (e.g. for IL6: 1.6 fold increase in MT4 vs 10.3 fold in NDL tumors). We then particularly focused on whether dendritic cell (DC) activation and CD4 T cell populations could be enhanced when ablating pancreatic tumors. By CIBERSORTx digital cytometry, aCD40 + aPD-1 combinations increased the presence of activated DCs in MT4 tumors by 2.4-fold. Activated DCs were also increased by CP4 (aCD40 + aPD-1 + CTLA-4) alone 1.7 fold or in combination with ablation in both treated (2.4 fold) and distant (2.2 fold) lesions. Ablation combined with aPD-1 alone did not significantly impact DCs in the MT4 model. In addition, CD4 lymphocytes increased 5 and 8 fold in treated and distant tumors by ablation combined with CP4 in the MT4 model. Taken together, inflammatory cytokines were preferentially elevated by ablation in a dense epithelial breast cancer as compared with a pancreatic tumor model. Further, the results suggest that aCD40 immunotherapy retains efficacy when combined with thermal ablation in pancreatic tumors. This work can inform clinical translation of ablative and immunotherapy combination protocols. Citation Format: James Wang, Brett Z. Fite, Aris Kare, Bo Wu, Marina N. Raie, Spencer Tumbale, Ryan R. Davis, Clifford G. Tepper, Katherine Ferrara. TME subtype impacts response to combined thermal ablation and immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6314.